E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital, hereditary and neonatal diseases |
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E.1.1.1 | Medical condition in easily understood language |
Congenital, hereditary and neonatal diseases |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036046 |
E.1.2 | Term | Polycystic kidney, autosomal dominant |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the effect of GZ/SAR402671 on the rate of total kidney volume (TKV) growth and eGFR in patients at risk of rapidly progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD) |
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E.2.2 | Secondary objectives of the trial |
-To determine the effect of GZ/SAR402671 on the rate of renal function decline (Stage 1) and on the rate of TKV growth (Stage 2).
-To evaluate the pharmacokinetics (PK) of GZ/SAR402671 in ADPKD patients (Stages 1 and 2).
-Safety/tolerability objective:
-To characterize the safety profile of GZ/SAR402671 (Stages 1 and 2).
-To evaluate the effect of GZ/SAR402671 on mood using Beck Depression Inventory II (BDI-II) (Stages 1 and 2).
-To evaluate the effect of GZ/SAR402671 on the lens by ophthalmological examination (Stages 1 and 2).
-To evaluate change in nocturia based on patient reported diary (Stages 1 and 2).
-To evaluate the effect of GZ/SAR402671 on kidney concentrating ability by assessing urine osmolality (in patients not on diuretic) (Stage 2 only). |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Measured Glomerular Filtration Rate Substudy
The main objective is to determine the effect of GZ/SAR402671 on mGFR.
Please refer to the clinical trial protocol EFC15392, version 1 dated 08-Feb-2018 (appendix A). |
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E.3 | Principal inclusion criteria |
-Male or adult female between ages of 18-50 years (both inclusive).
-Diagnosis of ADPKD by unified Pei criteria.
-Mayo Imaging Classification of Autosomal Dominant Polycystic Kidney Disease (ADPKD) Class 1C, 1D or 1E.
-Estimated glomerular filtration rate between 45-90 mL/min/1.73 m2 at screening (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]).
-Stable treatment regimen of antihypertensive therapy for at least 30 days prior to screening visit for hypertensive patient.
-Able to read, comprehend and respond to the study questionnaires.
-Able to provide a signed written informed consent.
- Patient does not have access to tolvaptan at the time of study start or tolvaptan is not indicated for treatment of patient according to treating physician (patient does not meet recommended criteria for treatment or does not tolerate treatment with tolvaptan).
-The patient, if female of childbearing potential, must have a negative blood pregnancy test [betahuman chorionic gonadotropin (β-hCG)] at the screening visit and a negative urine pregnancy test at the baseline visit.
-Sexually active female patients of childbearing potential and sexually mature male patients must agree to practice true abstinence in line with their preferred and usual lifestyle or to use 2 acceptable effective methods of contraception for the entire duration of the study and for at least 6
weeks for females and 90 days for males following their last dose of study drug. |
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E.4 | Principal exclusion criteria |
-Systolic blood pressure >160 mm Hg at Run-in and Baseline visits.
-History of administration of tolvaptan or other Polycystic Kidney Disease-modifying agents (somatostatin analogues) within 3 months prior to screening visit.
-Current participation in another investigational interventional study or use of investigational medicinal product (IMP), within 3 months or 5 half lives, whichever is longer, before randomization.
-The patient has a documented diagnosis of any of the following infections: hepatitis B, hepatitis C, human immunodeficiency virus 1 or 2. Patients with a positive hepatitis B surface antibody (HBsAb) test with a history of prior hepatitis B immunization are eligible if other criteria are met (ie, negative
tests for: HBsAg, hepatitis B core antibody [HBcAb], and hepatitis C virus antibody [HCVAb]).
-A history of drug and/or alcohol abuse within the past year prior to the screening visit.
-The patient is scheduled for in-patient hospitalization including elective surgery, during the study.
-The patient has a medical condition, including significant intercurrent illness or any other extenuating circumstance that may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities.
-The patient, in the opinion of the investigator, is unable to adhere to the requirements of the study or unable to undergo study assessments (eg, has contraindications to pupillary dilation or unable to undergo magnetic resonance imaging (MRI ) [For example: patient’s weight exceeds weight capacity of the MRI, ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, large abdominal/back tattoos, etc]).
-Any country-related specific regulation that would prevent the patient from entering the study.
-The patients did not adhere to treatment (<70% compliance rate) in the run-in.
-The patient has, according to World Health Organization (WHO) Grading, a cortical cataract >onequarter of the lens circumference (Grade cortical cataract-2 [COR-2]) or a posterior subcapsular cataract >2 mm (Grade posterior subcapsular cataract-2 [PSC-2]). Patients with nuclear cataracts will not be excluded.
-The patient is currently receiving potentially cataractogenic medications, including a chronic regimen (more frequently than every 2 weeks) of any route of corticosteroids (including medium and high potency topical steroids) or any medication that may cause cataract, according to the Prescribing Information.
-The patient has received strong or moderate inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives, whichever is longer, prior to randomization. This also includes the consumption of grapefruit, grapefruit juice, or grapefruit containing products within 72 hours of starting GZ/SAR402671 administration.
-The patient is pregnant, or lactating.
-Liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or total bilirubin >2 times the upper limit of normal unless the patient has the diagnosis of Gilbert syndrome.
-Presence of severe depression as measured by BDI-II >28 and/or a history of a major affective disorder within 1 year of the screening visit.
-Known hypersensitivity to GZ/SAR402671 or any component of the excipients. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Annualized rate of change in total kidney volume (TKV) based on magnetic resonance Imaging (MRI) from baseline to 18 months (Stage 1)
2. Annualized rate of change in estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease
Epidemiology Collaboration [CKD-EPI] equation) from baseline to 24 months (Stage 2) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From baseline to 18 months
2. From baseline to 24 months |
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E.5.2 | Secondary end point(s) |
1. Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 18 months (Stage 1) : From baseline to 18 months
2. Annualized rate of change in TKV based on MRI from baseline to 24 months (Stage 2) : From baseline to 24 months
3. Change in urine osmolality from baseline to 24 months (in patients not on diuretic) (Stage 2) : From baseline to 24 months
4. Change in nocturia from baseline to 18 months (Stage 1) and from baseline to 24 months (Stage 2) :
Stage 1: From baseline to 18 months
Stage 2: From baseline to 24 months
5. Number of adverse events (Stages 1 and 2) :
Stage 1: From baseline to 18 months
Stage 2: From baseline to 24 months
6. Assessment of single time-point plasma concentration (Stages 1 & 2) : Stage 1: Day 1, Months 1, 6, and 18
Stage 2: Months 6 and 24
7. Change in the lens clarity from baseline by ophthalmological examination (Stages 1 and 2) :
Stage 1: From baseline to 18 months
Stage 2: From baseline to 24 months |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to the section E.5.2. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
China |
Japan |
Korea, Republic of |
Taiwan |
United States |
France |
Netherlands |
Romania |
Spain |
Switzerland |
Czechia |
Germany |
Italy |
Belgium |
Denmark |
Portugal |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 2 |